Osteosarcoma
Sarcomas, malignancies of mesodermal origin, develop mainly in bone and soft tissues. McClay et al., "Immunotherapeutic Approaches to the Treatment of Bone and Soft Tissue Sarcomas", Seminars in Oncology 16, 328 (1989). Together, these tissues constitute greater than 60% of the adult body weight. McClay, "Epidemiology of Bone and Soft Tissue Sarcomas", Seminars in Oncology 16, 264 (1989). Despite this, the malignant degeneration of this tissue is rare. It is estimated that there were 2,000 new cases of bone sarcomas and 6,000 new cases of soft tissue sarcomas in 1994. American Cancer Society: Cancer Facts and Figures--1994, New York, American Cancer Society, 1994, p. 6. Together they constitute approximately 0.8% of all cancers diagnosed in the United States.
Although these sarcomas are not common, a significant number of patients who develop these tumors will die with metastatic disease. In fact, before 1972, the mortality for patients presenting with metastatic osteogenic sarcoma was 100%. Frei et al., "Osteogenic Sarcoma: The Development of Curative Treatment", In: Frontiers of Osteosarcoma Research Novak et al., eds., Hogrefe and Huber, pp. 5-13 (1993). For patients without metastatic disease, the majority required amputation to control the primary tumor and in spite of this, 80% of patients relapsed and died largely due to lung metastases. Bruland et al., "Immunoscintigraphy and Radioimmunotherapy: Useful Approaches in the Management of Osteogenic Sarcoma?", In: Frontiers of Osteosarcoma Research, Novak et al., eds., Hogrefe and Huber, pp. 149-159 (1993).
Relapse-free survival and overall survival have since been substantially increased by adjuvant chemotherapy. However, in spite of considerable progress in the treatment of patients with osteogenic sarcomas during the past 20 years, using regimens that include high-dose methotrexate, doxorubicin, and alkylating agents such as cyclophosphamide, ifosfamide and cisplatin, 40% of these patients still succumb to the disease. Ward et al., "Pulmonary Metastases of Stage IIB Extremity Osteosarcoma and Subsequent Pulmonary Metastases", Journal of Clinical Oncology, 12, 1849 (1994). Osteosarcoma patients relapsing after first-line treatment because of regrowth chemotherapy-resistant tumor cells seem to gain only marginal benefit from aggressive second-line chemotherapy.
Thus, patients with osteosarcoma require more effective detection and elimination of chemotherapy resistant disease. As mentioned above, adjuvant chemotherapy is a standard treatment approach for many sarcomas including Ewing's sarcoma, rhabdomyosarcoma, and osteosarcoma. Balis et al., "General Principals of Chemotherapy", In: Principles and Practice of Pediatric Oncology, 2nd ed., Pizzo et al. eds., J. B. Lippincott Company, Philadelphia, pp. 197-245 (1993). It has been more difficult, however, to demonstrate significant benefit of chemotherapy in adult soft tissue sarcomas and osteosarcoma with metastatic disease at diagnosis or after the development of lung metastases. Elias et al., "Adjuvant chemotherapy for soft tissue sarcoma: an approach in search of an effective regimen", Seminars in Oncology, 16, 305 (1989); Meyers et al., "Osteogenic sarcoma with clinically detectable metastasis at initial presentation", J. of Clinical Oncology 11, 449 (1993).
Drug targeting is a potentially attractive new approach to killing malignant cells, which leaves normal tissues unharmed. A breakthrough in drug targeting was the advent of hybridoma technology, making monoclonal antibodies (MoAb) available for clinical applications. To construct reagents with selectivity for certain populations of tumor cells, MoAbs or other cell targeting proteins are linked to cytotoxic agents to form molecules referred to as biotherapeutics which potentially combine the selectivity of the carrier moiety (e.g., MoAb) with the potency of the cytotoxic moiety. The choice of carrier moiety can be based on the surface antigen profile of a given malignant cell determined by reaction with an enzyme or fluorescently labelled antibody.
For the past decade, biotherapeutics have been under investigation for the treatment of various cancers, and more recently, for the treatment of immunological disorders such as rheumatoid arthritis and acquired immune deficiency syndrome (AIDS). Although these agents have shown some potential to provide safe and effective therapy for certain human pathologies, many difficulties remain. Ideally, consistently locatable and reliable markers on target cells would permit the binding portion of biotherapeutics to completely avoid binding to non-target tissue. In reality, cross-reactivity with antigens expressed by vital organs often gives rise to unacceptable complications in in vivo applications. There is also the potential that a patient will demonstrate immune responses to the separate components of the biotherapeutic agent, especially if they are not natural human proteins, even though the patient may already be immunosuppressed by the course of their disease. Moreover, the cytotoxicity obtained in in vitro studies may be limited in clinical application due to a lack of potency in doses that can be tolerated by the patient. Furthermore, solid tumors are difficult to penetrate thoroughly, resulting in the possibility of residual disease which can cause relapse. Finally, the rarity and heterogeneity of sarcomas has made the development of biotherapeutic agents against these cancers difficult. McClay, E. F., "Epidemiology of bone and soft tissue sarcomas", Seminars in Oncology 16, 264 (1989); McClay et al., "Immunotherapeutic approaches to the treatment of bone and soft tissue sarcomas", Seminars in Oncology, 16, 328, (1989).
Hence, there is a strong need to develop new treatment strategies for patients afflicted with sarcomas. Since the degree of necrosis of osteosarcoma in the neoadjuvant chemotherapy setting has been shown to be a highly significant predictor of disease free survival, a need further exists to increase the proportion of osteosarcoma patients with favorable initial responses to neoadjuvant chemotherapy as well as to develop novel treatments for patients with poor responses or metastatic disease. Raymond et al., "Osteosarcoma chemotherapy effect: A prognositc factor", Seminars in Diagnostic Pathology 4, 212 (1987); Winkler et al., "Neoadjuvant Chemotherapy of Osteosarcoma: Results of a Randomized Cooperative Triel (COSS-82) with Salvage Chemotherapy Based on Histologic Tumor Response", J. of Clinical Oncology 6, 329, (1988).